Dermal Delivery Compositions And Methods

ABSTRACT

A composition for transdermal delivery of a progestin for progestin hormone therapy is disclosed. Also disclosed is a transdermal delivery device comprising the composition. For progestin-only hormone therapy, the composition contains an anti-oxidant and does not contain an estrogen. For therapy involving a progestin and an estrogen, the composition contains the progestin, the estrogen and an additional anti-oxidant. Methods of improving the stability of progestin-containing compositions comprising oxidative agents are also disclosed. The methods comprise including one or more anti-oxidants in the compositions.

FIELD OF THE INVENTION

This invention is in the field of transdermal delivery of steroidhormones.

BACKGROUND OF THE INVENTION

Various adhesive matrix compositions have been developed for transdermaldelivery of steroid hormones. For example, U.S. Pat. No. 7,384,650describes a transdermal hormone delivery system that utilizes anadhesive composition comprising a pressure sensitive adhesive (PSA), ahumectant, a skin permeation enhancer, an estrogen and a progestin.

U.S. Patent Publications 2010/0292660 and 2010/0255072 describetransdermal delivery systems that can be used, among other ways, inconjunction with the PSA matrix described in U.S. Pat. No. 7,384,650.

The above-cited patent and patent applications are incorporated byreference as though fully set forth herein.

SUMMARY OF THE INVENTION

This invention relates to a polymeric matrix useful in a transdermaldelivery system for transdermal delivery of a progestin, in the absenceof an estrogen.

One aspect of the invention features composition for transdermaldelivery of a progestin that comprises: (a) a carrier, (b) a progestin,(c) a skin permeation enhancer and (d) an anti-oxidant, wherein thecomposition comprises a component that contributes to degradation of theprogestin, wherein the component is one or more of an organic solvent,polyvinyl pyrrolidone (PVP), or a PVP copolymer. In one embodiment, thecarrier is a polymeric pressure sensitive adhesive. In one embodiment,the component that contributes to degradation of the progestin is one ormore of PVP, polyvinyl pyrrolidone/vinyl acetate (PVP/VA), or dimethylsulfoxide (DMSO) and the anti-oxidant is not an estrogen or isadditional to an estrogen.

The progestin can be desogestrel, dihydroprogesterone, drospirenone,ethynodiol acetate, ethynodiol diacetate, etogestrel, gestodene,gestogen, 17-hydrogesterone, hydroxyprogesterone caproate,3-keto-desogestrel, levonorgestrel, medroxyprogesterone acetate,medroxyprogesterone diacetate, megestrol, megestrol acetate,normegesterol, norelgestromin, norethindrone (i.e., norethisterone),norethindrone acetate, norethynodrel, norgestimate, norgestrel,19-nortestosterone, progesterone, nestorone, methoxyprogesterone, ordl-norgestrel, or any combination of two or more of said progestins. Incertain embodiments, the progestin is levonorgestrel or norethindroneacetate.

The anti-oxidant is selected from Vitamins A, C, D, and E, carotenoids,flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene(“BHT”), butylated hydroxyanisole (BHA), glutathione, lycopene, gallicacid and esters thereof, salicylic acid and esters thereof, sulfites,alcohols, amines, amides, sulfoxides, surfactants, or any combinationthereof. In certain embodiments, the anti-oxidant is sodium bisulfite,sodium sulfite, isopropyl gallate, Vitamin C and E, Irganox 1010,Irgafos 168 or BHT or any combination of two or more of thoseanti-oxidants. In certain embodiments, the anti-oxidant comprises one ormore phenolic anti-oxidants. In particular, the anti-oxidant is BHT,pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), ortris(2,4-di-tert-butylphenyl) phosphite.

In certain embodiments, the polymeric carrier is a pressure sensitiveadhesive (PSA) selected from a polyacrylate adhesive, a polyisobutyleneadhesive, or a silicone adhesive. The PSA may be polymerized by freeradical polymerization. For instance, the PSA can be a polyacrylateadhesive. The PSA may comprise a 2-ethylhexyl acrylate co-monomer. Thepolyacrylate adhesive can further comprise about 50 to 60% w/w vinylacetate co-monomer.

In certain embodiments, the skin permeation enhancer comprises one ormore of: alcohols; alkanones; amides and other nitrogenous compounds;1-substituted azacycloheptan-2-ones; bile salts; cholesterol;cyclodextrins and substituted cyclodextrins; ethers; saturated andunsaturated fatty acids; saturated and unsaturated fatty acid esters;saturated and unsaturated fatty alcohol esters; glycerides andmonoglycerides; organic acids; methyl nicotinate; pentadecalactone;polyols and esters thereof phospholipids; sulfoxides; surfactants;terpenes; and combinations thereof. In one embodiment, the skinpermeation enhancer comprises an organic solvent. In some instances, theorganic solvent is DMSO. In certain embodiments, the skin permeationenhancer comprises one or more of: DMSO, a fatty (C₈-C₂₀) alcohol esterof a hydroxy acid, a lower (C₁-C₄) alkyl ester of a hydroxy acid, and aC₆-C₁₈ fatty acid. In a particular embodiment, the skin permeationenhancer comprises one or more of: DMSO, lauryl lactate, ethyl lactate,and capric acid.

The above-described composition can also include a humectant. In certainembodiments, the humectant is PVP or a PVP co-polymer, such as PVP/VA.

In various embodiments of the above-described composition, the progestinis present in a concentration based on weight of the composition of 0.1%to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%. The skin permeation enhancercan present in a concentration based on weight of the composition of 1%to 50% or 2% to 40%.

In certain embodiments, the anti-oxidant in the composition includesBHT. The BHT can be present in a concentration based on weight of thehormone of 10% to 500%, 20% to 200%, or 50% to 150%.

In certain embodiments, the composition may be one that does notcomprise an estrogen.

In certain embodiments, the anti-oxidant in the composition ispentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate) or tris (2,4-di-tert-butylphenyl) phosphite.

Another aspect of the invention features a transdermal drug deliverydevice that comprises: (a) a transdermal composition as summarizedabove, which comprises a PSA and has a skin contacting surface and anon-skin contacting surface; (b) a release liner adjacent the skincontacting surface of the transdermal composition; and (c) a backinglayer adjacent the non-skin contacting surface.

Another aspect of the invention features a method of improving thestability of a progestin-only transdermal delivery composition thatincludes an oxidizing agent. The method comprises adding an anti-oxidantother than an estrogen to the composition. In certain embodiments, theoxidizing agent is one or more of an organic solvent, PVP, or a PVPcopolymer. In certain embodiments, the composition comprises a PSA. Theprogestin can be desogestrel, dihydroprogesterone, drospirenone,ethynodiol acetate, ethynodiol diacetate, etogestrel, gestodene,gestogen, 17-hydrogesterone, hydroxyprogesterone caproate,3-keto-desogestrel, levonorgestrel, medroxyprogesterone acetate,medroxyprogesterone diacetate, megestrol, megestrol acetate,normegesterol, norelgestromin, norethindrone (norethisterone),norethindrone acetate, norethynodrel, norgestimate, norgestrel,19-nortestosterone, progesterone, nestorone, methoxyprogesterone, anddl-norgestrel or any combination of two or more of said progestins. Inparticular, the progestin is levonorgestrel or norethindrone acetate.

In certain embodiments of the method, the anti-oxidant is selected fromVitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids,beta-carotene, butylated hydroxytoluene (“BHT”), butylatedhydroxyanisole (BHA), glutathione, lycopene, gallic acid and estersthereof, salicylic acid and esters thereof, sulfites, alcohols, amines,amides, sulfoxides, phenolics or surfactants, or any combination of twoor more of said anti-oxidants. In particular, the anti-oxidant is sodiumbisulfite, sodium sulfite, isopropyl gallate, Vitamin C and E, Irganox1010, Irgafos 168 or BHT or any combination of two or more of saidanti-oxidants.

In certain embodiments of the method, the polymeric carrier is a PSAselected from a polyacrylate adhesive, a polyisobutylene adhesive, or asilicone adhesive. The PSA may be polymerized by free radicalpolymerization. For instance, the PSA may be a polyacrylate adhesive.The PSA can comprise a 2-ethylhexyl acrylate monomer. The polyacrylateadhesive can further comprises about 3 to 60% w/w vinyl acetate monomer.

In various embodiments of the method, the skin permeation enhancer inthe composition comprises one or more of: alcohols; alkanones; amidesand other nitrogenous compounds; 1-substituted azacycloheptan-2-ones;bile salts; cholesterol; cyclodextrins and substituted cyclodextrins;ethers; saturated and unsaturated fatty acids; saturated and unsaturatedfatty acid esters; saturated and unsaturated fatty alcohol esters;glycerides and monoglycerides; organic acids; methyl nicotinate;pentadecalactone; polyols and esters thereof; phospholipids; sulfoxides;surfactants; terpenes; and combinations thereof. In certain embodiments,the enhancer comprises an organic solvent. In particular, the organicsolvent is DMSO. In certain embodiments, the enhancer comprises one ormore of: DMSO, a fatty (C₈-C₂₀) alcohol ester of a hydroxy acid, a lower(C₁-C₄) alkyl ester of a hydroxy acid, and a C₆-C₁₈ fatty acid. Inparticular, the enhancer comprises DMSO, lauryl lactate, ethyl lactate,and capric acid.

In certain embodiments of the method, the composition further comprisesa humectant. The humectant may be PVP or a PVP co-polymer, such asPVP/VA.

In various embodiments of the method, the progestin is present in thecomposition in a concentration based on weight of the composition of0.1% to 3.0% or 0.2% to 2.0% or 0.5% to 1.5%. The skin permeationenhancer is present in a concentration based on weight of thecomposition of 1% to 50% or 2% to 40%.

In various embodiments of the method, the anti-oxidant in thecomposition is BHT. The BHT may present in a concentration based onweight of the hormone of 10% to 500%, 20% to 200%, or 50% to 150%.

In various embodiments of the method, the anti-oxidant in thecomposition is pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate) or tris(2,4-di-tert-butylphenyl) phosphite.

These and other embodiments, which are more fully described below, aremeant to be illustrative and not limiting of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is useful in delivering a progestin hormone to apatient that can benefit from progestin-only hormone supplementation,i.e., delivery of a progestin with or without concomitant delivery of anestrogen. In an aspect of the present invention, the progestin, inparticular, levonorgestrel, is stabilized, i.e., protected fromdegradation, by incorporation of an anti-oxidant. While ethinylestradiol itself has anti-oxidizing activity, it is contemplated inaccordance with this invention that if an estrogen is present, then afurther anti-oxidant that is not an active pharmaceutical ingredient,e.g., that is not ethinyl estradiol or other hormone, is included in thetransdermal composition.

As discussed further hereinbelow, certain components of a transdermalcomposition, such as the transdermal compositions described in U.S. Pat.No. 7,384,650 and hereinbelow, have been found to contribute todegradation of levonorgestrel. Such components include the polyacrylatepressure sensitive adhesive (“PSA”), the PVP humectant (e.g., PVP/VA),and the dimethyl sulfoxide skin permeation enhancer. Incorporation of anexcipient that functions as an anti-oxidant can protect the progestinfrom degradation, i.e., it can slow degradation of the progestin, andthereby increase the shelf life of the composition.

Progestin-Containing Transdermal Composition:

The composition for transdermal delivery, i.e., systemic deliverythrough the skin, comprises a progestin, an anti-oxidant, a skinpermeation enhancer and a carrier. The composition does not necessarilycomprise an estrogen, If it does not, it may be referred to as a“progestin-only transdermal composition”. The composition optionallyalso comprises excipients such as gelling agents, plasticizers,humectants, buffers, and the like. The composition can be formulated andapplied to the skin, for instance, as a gel, an ointment, or a spray, orit can be contained within a transdermal delivery device, such as apatch, in which the composition is contained, for example, within areservoir by a semi-permeable membrane or as a soft polymeric matrixthat is in direct contact with the skin, i.e., that is firm enough thata reservoir membrane is not required.

In an illustrative embodiment of the invention, the composition is apolymeric matrix comprising a polymer such as a pressure-sensitiveadhesive (PSA) as a carrier, the progestin, the anti-oxidant and theskin permeation enhancer. The polymer can be a pressure sensitiveadhesive (“PSA”) that forms a biologically acceptable adhesive polymermatrix capable of forming adhesive active-containing thin films orcoatings through which the progestin can pass into the skin. Suitablepolymers are biologically and pharmaceutically compatible,nonallergenic, insoluble in and compatible with body fluids or tissueswith which the device is contacted. The use of water soluble polymers isgenerally less preferred since dissolution or erosion of the matrixwould affect the release rate of the progestin as well as the capabilityof the dosage unit to remain in place on the skin. So, in certainembodiments, the polymer is non-water soluble.

Suitable progestin transdermal compositions are disclosed, e.g., in U.S.Pat. No. 7,045,145, U.S. Pat. No. 7,384,650, US 20100255072, US2010292660, and US 20100178323, all of which are incorporated herein byreference as though fully set forth.

Polymers used to form a polymer matrix in the progestin-containing layercan have glass transition temperatures below room temperature such thatthey are soft and pliable at room temperature. The polymers arepreferably non-crystalline but may have some crystallinity if necessaryfor the development of other desired properties. Cross-linkablemonomeric units or sites can be incorporated into such polymers. Forexample, cross-linking monomers that can be incorporated intopolyacrylate polymers include polymethacrylic esters of polyols such asbutylene diacrylate and dimethacrylate, trimethylol propanetrimethacrylate and the like. Other monomers that provide such sitesinclude allyl acrylate, allyl methacrylate, diallyl maleate and thelike.

PSAs that can be used to form the adhesive composition are typicallypolyacrylate, polyisobutylene, or silicone adhesives. A useful adhesivepolymer formulation comprises a polyacrylate adhesive polymer of thegeneral formula (I):

wherein X represents the number of repeating units sufficient to providethe desired properties in the adhesive polymer and R is H or a lower(C₁-C₁₀) alkyl, such as ethyl, butyl, 2-ethylhexyl, octyl, decyl and thelike. The adhesive polymer matrix can comprise, for instance, apolyacrylate adhesive copolymer having a 2-ethylhexyl acrylate monomerand approximately 50-60% w/w of vinyl acetate as a co-monomer. Anexample of a suitable polyacrylate adhesive copolymer for use in thepresent invention includes, but is not limited to, that sold under thetradename of Duro Tak® 87-4098 by Henkel Corporation, Bridgewater, N.J.,which comprises vinyl acetate co-monomer.

Progestins:

Progestins useful in the practice of the present invention includedesogestrel, dihydroprogesterone, drospirenone, ethynodiol acetate,ethynodiol diacetate, etogestrel, gestodene, gestogen,17-hydrogesterone, hydroxyprogesterone caproate, 3-keto-desogestrel,levonorgestrel, medroxyprogesterone acetate, medroxyprogesteronediacetate, megestrol, megestrol acetate, normegesterol, norelgestromin,norethindrone (i.e., norethisterone), norethindrone acetate,norethynodrel, norgestimate, norgestrel, 19-nortestosterone,progesterone, nestorone, methoxyprogesterone, and dl-norgestrel or anycombination of two or more of said progestins. Of particular interestare levonorgestrel and norethindrone and norethindrone salts, e.g.,norethindrone acetate. Levonorgestrel is a potent progestin on aweight-dose basis and may be selected for that or other reasons. Theprogestin is typically present in a concentration based on weight of thetransdermal composition (i.e., wt %) of 0.1 to 3% or 0.2 to 2.0% or0.5-1.5%.

Estrogens:

Estrogens useful in the practice of the present invention include,without limitation, ethinyl estradiol, 17-beta-estradiol,estradiol-3,17-diacetate; estradiol-3-acetate; estradiol 17-acetate;estradiol-3,17-divalerate; estradiol-3-valerate; estradiol-17-valerate;3-mono-, 17-mono- and 3,17-dipivilate estradiol esters; 3-mono-,17-mono- and 3,17-dipropionate estradiol esters; 3-mono-, 17-mono- and3,17-dicyclo pentyl-propionate estradiol esters, and estrone. Ofparticular interest is ethinyl estradiol. The estrogen is typicallypresent in a concentration based on weight of the transdermalcomposition (i.e., wt %) of 0.1 to 3% or 0.2 to 2.0% or 0.5 to 1.5%,e.g., 0.5 to 1%.

Skin Permeation Enhancers:

A number of skin permeation enhancers have been used to improve passageof progestins through the skin and into the blood stream. These include,e.g., alcohols; alkanones; amides and other nitrogenous compounds;1-substituted azacycloheptan-2-ones; bile salts; cholesterol;cyclodextrins and substituted cyclodextrins; ethers; saturated andunsaturated fatty acids; saturated and unsaturated fatty acid esters;saturated and unsaturated fatty alcohol esters; glycerides andmonoglycerides; organic acids; methyl nicotinate; pentadecalactone;polyols and esters thereof; phospholipids; sulfoxides; surfactants;terpenes; and combinations thereof.

As specific examples, the following can be mentioned: decanol,dodecanol, 2-hexyl decanol, 2-octyl dodecanol, oleyl alcohol,undecylenic acid, lauric acid, myristic acid and oleic acid, fattyalcohol ethoxylates, esters of fatty acids with methanol, ethanol orisopropanol, methyl laurate, ethyl oleate, isopropyl myristate andisopropyl palmitate, esters of fatty alcohols with acetic acid or lacticacid, lauryl lactate, oleyl acetate, 1,2-propylene glycol, glycerol,1,3-butanediol, dipropylene glycol and polyethylene glycols.

Of particular interest are volatile organic solvents, including, but notlimited to, dimethyl sulfoxide (DMSO), C₁-C₈ branched or unbranchedalcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol,and the like, as well as azone (laurocapram:1-dodecylhexahydro-2H-azepin-2-one) and methylsulfonylmethane. Also ofparticular interest are fatty acids and esters thereof.

For example, a skin permeation enhancer useful in the present inventioncan be a mixture of (1) a pharmaceutically acceptable organic solvent,such as dimethyl sulfoxide (DMSO), (2) a fatty (C₈-C₂₀) alcohol ester ofa hydroxy acid, such as lauryl lactate, (3) a lower (C₁-C₄) alkyl esterof a hydroxy acid, e.g., ethyl lactate, and (4) a C₆-C₁₈ fatty acid,such as capric acid. In specific embodiments, the fatty alcohol ester oflactic acid is lauryl lactate and the lower alkyl ester of lactic acidis ethyl lactate. A medium- to long-chain fatty acid in the skinpermeation enhancer formulation can be employed among the skinpermeation enhancers. Capric acid is preferred for use but other C₆-C₁₈saturated or unsaturated fatty acids may be used, including but notlimited to caproic acid, caprylic acid, lauric acid and myristic acid,to name a few.

In a particular embodiment, the pharmaceutically acceptable organicsolvent is DMSO. Other organic solvents suitable for use in the presentinvention include, but are not limited to, C₁-C₈ branched or unbranchedalcohols, such as ethanol, propanol, isopropanol, butanol, isobutanol,and the like, as well as azone (laurocapram:1-dodecylhexahydro-2H-azepin-2-one) and methylsulfonylmethane, to name afew.

The fatty alcohol ester of a hydroxy acid can be a fatty alcohol esterof lactic acid, such as lauryl lactate. However, other hydroxy acids andfatty alcohols may be utilized. Alternative hydroxy acids include, butare not limited to, alpha-hydroxy acids such as glycolic acid, tartaricacid, citric acid, malic acid and mandelic acid, as well as thebeta-hydroxy acid, salicylic acid. Alternative fatty alcohols includeany C₈-C₂₀ saturated or unsaturated fatty alcohols, such as myristyl,palmityl or oleyl alcohols, to name a few.

The lower alkyl ester of hydroxy acid can also utilize lactic acid, andcan be, e.g., ethyl lactate. However, other hydroxy acids, such asglycolic acid, tartaric acid, citric acid, malic acid, mandelic acid andsalicylic acid, may also be utilized. In addition isopropylmyristic acid(IPM) may be used as a substitute for the lower alkyl ester of hydroxyacid.

The aforementioned combination of skin permeation enhancers may be usedto enhance transdermal delivery of steroid hormones from any type oftransdermal delivery composition, as discussed above. An adhesivepolymer matrix-type system as described in detail herein and in U.S.Pat. No. 7,045,145, U.S. Pat. No. 7,384,650, US 20100255072, US2010292660, and US 20100178323 are illustrative; however, the enhancercombination may also be utilized in non-adhesive polymers, as well as inmulti-layer or reservoir-type transdermal delivery systems, gels,ointments, sprays, and lotions, to name a few.

The skin permeation enhancer is typically present in a concentration ofat least 1% or at least 2% by weight of the composition. It may bepresent in a concentration of up to 50% or up to 40% by weight of thecomposition. In certain embodiments, the skin permeation enhancer ispresent in a concentration based on weight of the composition (i.e., wt%) of 1 to 50% or 10 to 40% or 20 to 30% of the composition.

Optional Additional Excipients:

A number of excipients are employed in transdermal delivery compositionsfor various purposes. Of particular interest are polymers that functionas humectants and/or as plasticizers. Incorporation of a humectant inthe formulation allows the dosage unit to absorb moisture from thesurface of skin, which in turn helps to reduce skin irritation and toprevent the adhesive polymer matrix of the delivery system from failingto adhere for a sufficient duration. The plasticizer/humectant may be aconventional plasticizer used in the pharmaceutical industry, forexample, polyvinyl pyrrolidone (PVP). In particular, PVP/vinyl acetate(PVP/VA) co-polymers, such as those having a molecular weight of fromabout 50,000, are suitable for use in the present invention. The PVP/VAacts as both a plasticizer, acting to control the rigidity of thepolymer matrix, as well as a humectant, acting to regulate moisturecontent of the matrix. The PVP/VA can be, for example, Plasdone® S-630Copovidone (International Specialty Products, Inc. (ISP), Wayne, N.J.),which is a 60:40 PVP:VA co-polymer that has a molecular weight of 24,000to 30,000 and a glass transition temperature of 106° C. The amount ofhumectant/plasticizer is directly related to the duration of adhesion ofthe overlay.

Anti-Oxidants:

Anti-oxidants function to prevent or inhibit oxidation of othermolecules by themselves becoming oxidized. In a polymeric matrixcomprising both a progestin and an estrogen such as ethinyl estradiol,the ethinyl estradiol functions as an anti-oxidant and thereby helps toreduce oxidative degradation of the progestin. Employment of anadditional anti-oxidant further reduces oxidative degradation. In aprogestin-only composition, employment of an anti-oxidant can be evenmore important.

For example, certain polymers, in particular, polymers formed by freeradical polymerization, have been found to act as oxidizing agents in apolymeric matrix comprising a progestin, whereby the stability of theprogestin is compromised. For example, it has been discovered inaccordance with the present invention that polyacrylate adhesives causeoxidation of a progestin, e.g., levonorgestrel.

It has also been discovered in accordance with the present inventionthat PVP, which is commonly used in transdermal polymeric compositions,also contributes to oxidation of a progestin. Therefore, in transdermalcompositions comprising PVP, or PVP/VA, and a progestin, addition of ananti-oxidant improves the stability of the progestin.

It has also been discovered in accordance with the present inventionthat certain permeation enhancers, e.g., DMSO, can also cause oxidationof a progestin, e.g., levonorgestrel.

Thus, one aspect of the invention features a polymeric matrix comprisingthe progestin, the anti-oxidant, the skin permeation enhancer and apressure sensitive adhesive (“PSA”), wherein the PSA is a polyacrylateadhesive, e.g., a polyacrylate/vinyl acetate copolymer such as Duro Tak®87-4098, and/or wherein the polymeric matrix comprises PVP or PVP/VA,and/or wherein the permeation enhancer comprises DMSO.

A number of compounds can act as anti-oxidants in the transdermalcomposition of the present invention. Among compounds known to act asanti-oxidants are: Vitamins A, C, D, and E, carotenoids, flavanoids,isoflavanoids, beta-carotene, butylated hydroxytoluene (“BHT”),butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid andesters thereof, salicylic acid and esters thereof, sulfites, alcohols,amines, amides, sulfoxides, surfactants, etc. Of particular interest arephenolic anti-oxidants, e.g., BHT, pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), e.g., Irganox1010, and tris(2,4-di-tert-butylphenyl) phosphite, e.g., Irgafos 168, aswell as sodium bisulfate, sodium sulfite, isopropyl gallate, Vitamin Cand Vitamin E.

Phenolic anti-oxidants, like BHT, which are sometimes referred to asprimary anti-oxidants, are particularly suitable. Larger phenolicanti-oxidants, e.g., molecular weight greater than 500 (e.g.,tris(2,4-di-tert-butylphenyl) phosphite) or greater than 1000 (e.g.,pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate) may beutilized to advantage.

The pH of the transdermal composition can be maintained at about pH 6 toabout pH 8, e.g., at about pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 or 8.0. Inone embodiment, the composition is maintained at about pH 6.5 to pH7.5.In another embodiment, the composition is maintained at about pH 7.Anti-oxidants that would increase pH, e.g., sodium metabisulfite, arepreferably avoided. BHT can be present, e.g., in a concentration basedon the weight of the hormone of at least 10 wt % or at least 20 wt % orat least 30 wt % of the hormone. BHT can be present, e.g., in aconcentration of up to 150 wt % or 200 wt % or 500 wt % of the hormone.In certain embodiments, BHT is present in a concentration based onweight of the hormone of 10 to 500%, 20 to 200%, or 50 to 150% of thehormone. Suitable concentrations of other anti-oxidants are readilyascertainable. For example, suitable concentrations oftris(2,4-di-tert-butylphenyl) phosphite, e.g., Irgafos 168, includeconcentrations that are similar to those of BHT, although lower orhigher concentrations may also be employed; suitable concentrations ofpentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), e.g., Irganox 1010, include similar concentrations althoughlower or higher concentrations may be employed, e.g., concentrationsthat are up to about 10%, 20% or 30% higher.

The following examples are set forth to describe the invention ingreater detail. They are intended to illustrate, not limit, theinvention.

EXAMPLES Example 1

A master blend, utilizing the formula listed in Table 1, below, wasproduced. The master blend was divided and spiked with ethinyl estradiolor known anti-oxidants as shown in Table 3. Each blend was then coatedon a release liner at a target coat weight of 133 g/m² and dried at 60°C. The sheets were laminated, cut into 15 cm² samples, placed betweentwo release liners, pouched, and then stored at 80° C. Samples wereevaluated at five time points as shown in Table 2.

TABLE 1 Master Blend Formula Levonorgestrel 0.38% Penetration Enhancers,39.0% PVP/VA, Ethyl Acetate PSA* 60.5% *PSA = polyacrylate adhesivecopolymer having a 2-ethylhexyl acrylate monomer and approximately50-60% w/w of vinyl acetate as a co-monomer

TABLE 2 Sampling Plan Sampling Time Point Temperature Number of SamplesTested 0 days (T₀) 80° C. 3 2 days (T₂) 80° C. 3 4 days (except Batch 7)(T₄) 80° C. 3 6 days (Batch 7 only) (T₆) 80° C. 3 8 days (T₈) 80° C. 3

TABLE 3 Test Blends Batch #1 Master Blend Batch #2 Master Blend +ethinyl estradiol, 1.53 mg/15 cm² Batch #3 Master Blend + BHT, 1.14mg/15 cm² Batch #4 Master Blend + BHT, 1.71 mg/15 cm² Batch #5 MasterBlend + Irganox 1010, 1.11 mg/15 cm² + Irgafos 168, 0.57 mg/15 cm² Batch#6 Master Blend + Irganox 1010, 1.66 mg/15 cm² + Irgafos 168, 0.85 mg/15cm² Batch #7 Master Blend + ethinyl estradiol, 0.97 mg/15 cm²

The amounts of levonorgestrel in each composition at each time point areshown in Table 4 as an average of 3 samples of each batch as apercentage of the target amount of levonorgestrel (“% TL”), which is0.868% based on the weight of the polymeric matrix.

TABLE 4 Levonorgestrel Stability as % Target Levonorgestrel Batch T₀ T₂T₄ T₆ T₈ Batch 1 96.9 87.1 68.5 NA 48.1 Batch 2 106.6 92.8 93.3 NA 87.3Batch 3 106.8 102.0 98.1 NA 97.7 Batch 4 103.4 102.2 99.7 NA 95.7 Batch5 104.3 104.3 99.4 NA 94.6 Batch 6 102.6 101.1 98.5 NA 93.1 Batch 7105.4 97.1 NA 93.4 91.7

These results demonstrate that ethinyl estradiol functions as ananti-oxidant in the composition and that levonorgestrel stability ismarkedly improved by addition of an anti-oxidant to the composition.

Example 2

To six batches of a master blend of levonorgestrel, penetrationenhancers, polyvinylpyrrolidone/vinyl acetate copolymer, and pressuresensitive adhesive, substantially as described in Example 1, BHT wasadded at different amounts ranging from 0.02 mgs per patch (each patchcontains 300 mgs of master blend) to 1.7 mgs per patch (the value of 1.7mgs represents the molar equivalent of the amount of levonorgestrel ineach patch).

Each batch was heated to 80° C. and analyzed at the time points of 0, 4and 8 days. All BHT loading values had a positive effect on thestability of levonorgestrel. The amounts of LNG remaining at T=Day 0,T=Day 4, and T=Day 8 are shown in Table 5.

TABLE 5 Effect of BHT concentration on the degradation of levonorgestrelBHT (mg/patch) Day 0 Day 4 Day 8 0 98 56 56 1.7 100 95 91 0.3 102 98 910.15 101 94 85 0.075 98 90 69 0.040 101 74 62 0.020 100 66 66

Example 3

The following test batches were prepared and tested as described.

a) Levonorgestrel (2.6 mg) was dissolved in 412 mg Duro Tak 87-4098(hereinbelow, “Carrier”). Drawdowns were made and heated at 80° C. for 4and 8 days. The amounts of levonorgestrel remaining and the percent ofdegradants for the samples heated at 4 and 8 days were determined.b) Levonorgestrel (2.6 mg) and 60 mg of PVP/VA were dissolved in 412 mgof Carrier. Drawdowns were made and heated at 80° C. for 4 and 8 days.The amounts of levonorgestrel remaining and the percent of degradantsfor the samples heated at 4 and 8 days were determined.c) Levonorgestrel (2.6 mg), 1.71 mg BHT and 60 mg PVP/VA were dissolvedin 412 mg Carrier. Drawdowns were made and heated at 80° C. for 4 and 8days. The amounts of levonorgestrel remaining and the percent ofdegradants for the samples heated at 4 and 8 days were determined.d) The same procedure as described in c) was performed, except 1.14 mgBHT was added.

The batch formulations are summarized in Table 6.

TABLE 6 Summary of Batch Formulations Carrier levonorgestrel PVP/VA BHT(mg) (mg) (mg) (mg) a 412 2.6 b 412 2.6 60 c 412 2.6 60 1.71 d 412 2.660 1.14

HPLC analysis was conducted to identify degradants of levonorgestrel. Analiquot of approximately 200 mg and 100 mg of the sample (exact weightrecorded) for 4 and 8 day stability was used. The sample was dissolvedin 5 mL of 1:1 tetrahydrofuran:methanol (THF/MeOH). 10 μL was injectedfor HPLC analysis.

Levonorgestrel degradants appeared after incubation in the 80° C. ovenfor 4 days and 8 days for samples a and b. No degradant was found forsamples c and d. The results are shown in Table 7.

TABLE 7 Peak Area Percentage of Total Degradants Total degradants (%)Sample ID 4 day 8 day A 0.48 0.75 B 1.26 1.28 C 0.00 0.00 D 0.00 0.00

The peak area percentages of remaining levonorgestrel after incubationin 80° C. oven are shown in Table 8.

TABLE 8 Peak Area Percentage of Remaining Substances Remaining RemainingSample ID 4 day 8 day a 99.52 99.25 b 98.74 98.72 c 100.00 100.00 d100.00 100.00

Note for Table 8: Remaining levonorgestrel percentages were directlyobtained from peak area percentages.

The force degradation study described above indicated that addition ofBHT reduced degradation of levonorgestrel, while addition of Povidone(PVP) slightly increased the degradation.

Example 4

Transdermal delivery patches were prepared comprising penetrationenhancers, polyvinylpyrrolidone/vinyl acetate copolymer, pressuresensitive adhesive, and varying amounts of levonorgestrel (LNG) and BHT,as follows:

Lot 1: LNG (2.17 mg, 0.87 wt %)−12.5 cm² patch;Lot 2: LNG (2.6 mg, 0.87 wt %) plus BHT (1.712 mg, 0.57 wt %)−15 cm²patch;

Skin flux across human cadaver skin (3 donor skin samples, 3 replicatesper skin donor) was compared. Data are reported in Table 9.

TABLE 9 Cumulative amounts of LNG permeated as a function of time. LotCumulative amounts of LNG permeated (ug/cm²) # 24 h 48 h 72 h 96 h 120 h144 h 168 h 1 5.503 +/− 1.475 12.414 +/− 2.456 18.787 +/− 3.256 24.962+/− 3.895 30.502 +/− 4.569 35.767 +/− 5.230 40.736 +/− 5.770 2 5.187 +/−1.900 11.336 +/− 2.755 17.092 +/− 3.578 22.650 +/− 4.286 27.795 +/−4.969 32.689 +/− 5.551 37.355 +/− 6.110

The mean steady-state flux of levonorgestrel (ug/cm²/h) in each batch isshown in the following table.

TABLE 10 Mean steady-state flux of levonorgestrel (ug/cm²/h) Lot 10.2442 +/− 0.0312 Lot 2 0.2231 +/− 0.0312

These data show that permeation of levonorgestrel was not impeded by theaddition of BHT.

Example 5

As shown in Table 11, seven transdermal compositions, each comprisingapproximately 164.8 mg Duro Tak® 87-4098 and 2.6 mg levonorgestrel(LNG), after drying, with and without PVP/VA and DMSO, were prepared totest the oxidative effects of a polyacrylate PSA, PVP, and DMSO.

TABLE 11 Compositions Composition # PVP/VA (mg) DMSO (mg) 1 None none 260 mg PVP/VA none 3 60 mg PVP/VA none 4 60 mg PVP/VA none 5 60 mg PVP/VAnone 6 None 16 mg DMSO 7 60 mg PVP/VA 16 mg DMSO

In the case of compositions 1-4 and 6, the PSA was pre-heated at 78° C.for 8 hours prior to addition of PVP/VA and DMSO. In the case ofpreparations 3 and 4, the PVP/VA was pre-heated at 80° C. for 48 hoursin the presence of air and nitrogen, respectively.

All preparations were then placed in an oven at 80° C. for 4 days and 8days. Degradants were analyzed by HPLC. Degradant percentage data areprovided in Table 12.

TABLE 12 Peak Area Percentage of Total Degradants Degradants (%)Degradants (%) Composition # Day 4 Day 8 1 0.32 0.47 2 0.76 0.94 3 0.870.91 4 0.78 1.16 5 1.21 1.60 6 1.12 1.67 7 1.65 1.78

As shown in Table 12, presence of PVP/VA increased degradants roughly bytwo-fold. Pre-treatment of PVP/VA did not show significant difference.Heating the compositions for 8 days produced slightly more degradantsthan for 4 days. Pre-heating the PSA reduced the amount of degradants.Addition of DMSO increased the amount of degradants.

Example 6

A master blend utilizing the formula listed in Table 13 was produced.The master blend was then divided and spiked with BHT as shown in Table14. Each test blend was then coated on a release liner at a target coatweight of 200 g/m² and dried at 60° C. for 17.5 mins using a fan speedof 2300 rpm. The sheets were then laminated, cut into 15 cm² samples,placed between two release liners, pouched, and then stored at 80° C.Samples were evaluated on Days 0, 4, and 8.

TABLE 13 Master Blend Formula Levonorgestrel 0.378% Ethinyl estradiol0.333% Penetration Enhancers, 39.558% PVP/VA, Ethyl Acetate PSA* 59.730%*PSA = polyacrylate adhesive copolymer having a 2-ethylhexyl acrylatemonomer and approximately 50-60% w/w of vinyl acetate as a co-monomer[Duro-Tak 87-4098]

TABLE 14 Test Blends Batch #1 Master Blend Batch #2 Master Blend + BHT,1.712 mg/15 cm², 2.481 g/kg Batch #3 Master Blend + BHT, 1.000 mg/15cm², 1.449 g/kg Batch #4 Master Blend + BHT, 0.428 mg/15 cm², 0.620 g/kgBatch #5 Master Blend + BHT, 0.300 mg/15 cm², 0.435 g/kg Batch #6 MasterBlend + BHT, 0.150 mg/15 cm², 0.217 g/kg

The amounts of levonorgestrel and ethinyl estradiol were determined byHPLC. The results (% LC) for each test blend are shown in Table 15 as anaverage of 5 samples per test blend, with %-Relative Standard Deviations(% RSD).

TABLE 15 Results Day 0 Day 4 EE EE Day 8 (% LNG (% LNG EE LNG Test BlendRSD) (% RSD) RSD) (% RSD) (% RSD) (% RSD) Control 98.7 100.3 77.3 43.072.9 28.5 (1.9) (2.1) (1.0) (3.1) (9.1) (57.0) 2 98.0 98.7 91.4 72.185.4 57.5 (2.2) (2.2) (1.3) (1.5) (2.4) (8.1) 3 99.1 99.6 87.8 66.7 86.954.4 (1.8) (2.0) (2.6) (2.1) (2.6) (22.8) 4 99.3 100.2 85.7 51.6 79.833.9 (3.1) (3.0) (3.0) (9.4) (5.9) (48.6) 5 97.4 98.2 81.0 54.7 82.641.8 (1.8) (1.9) (1.8) (6.4) (3.3) (33.6) 6 98.5 99.6 80.4 38.9 81.041.5 (1.2) (1.1) (6.1) (51.5) (1.6) (7.1)

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application and thescope of the appended claims.

1. An adhesive polymer matrix composition for transdermal delivery oflevonorgestrel, wherein: (a) the composition comprises thelevonorgestrel, an anti-oxidant, and a skin permeation enhancer in apolyacrylate pressure sensitive adhesive (PSA); (b) the compositioncomprises at least one component that contributes to oxidativedegradation of the levonorgestrel, wherein the at least one component isone or more of (i) the polyacrylate PSA, (ii) the skin permeationenhancer wherein the enhancer comprises dimethyl sulfoxide (DMSO), and(iii) polyvinyl pyrrolidone (PVP) or a PVP copolymer; (c) (i) theanti-oxidant is not an estrogen; (ii) the anti-oxidant is not asulfoxide or a fatty acid; and (iii) the anti-oxidant protects againstoxidative degradation of the levonorgestrel by the one or more of thePSA, the DMSO and the PVP or PVP copolymer; and (d) the stability of thecomposition is improved over the stability of such composition lackingthe anti-oxidant.
 2. The composition of claim 1 that lacks an estrogen.3. The composition of claim 1, wherein the anti-oxidant is selected fromVitamins A, C, D, and E, carotenoids, flavanoids, isoflavanoids,beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole(BHA), glutathione, lycopene, gallic acid and esters thereof, salicylicacid and esters thereof, sulfites, or any combination thereof.
 4. Thecomposition of claim 3 that lacks an estrogen.
 5. The composition ofclaim 1 wherein the anti-oxidant is selected from sodium bisulfite,sodium sulfite, isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT,pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate),tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 6.The composition of claim 5 that lacks an estrogen.
 7. The composition ofclaim 1, wherein the polyacrylate PSA contributes to oxidativedegradation of the levonorgestrel.
 8. The composition of claim 1,wherein the skin permeation enhancer is DMSO and the DMSO contributes tothe oxidative degradation of the levonorgestrel.
 9. The composition ofclaim 8 that lacks an estrogen.
 10. The composition of claim 1, whereinthe PVP or PVP copolymer contributes to the oxidative degradation of thelevonorgestrel and the PVP copolymer is PVP/vinyl acetate (PVP/VA). 11.The composition of claim 10 that lacks an estrogen.
 12. The compositionof claim 1, further comprising one or more other skin permeationenhancers selected from a fatty (C₈-C₂₀) alcohol ester of a hydroxylacid, a lower (C₁-C₄) alkyl ester of a hydroxyl acid, and a C₆-C₁₈ fattyacid.
 13. The composition of claim 12 that lacks an estrogen.
 14. Thecomposition of claim 1, disposed within a transdermal delivery devicethat comprises a skin contacting surface and a non-skin contactingsurface, a release liner adjacent the skin contacting surface and abacking layer adjacent the non-skin contacting surface.
 15. A method ofimproving the stability of a transdermal delivery composition comprisinglevonorgestrel, the method comprising adding an anti-oxidant other thanan estrogen to the composition; wherein (a) the composition comprisesthe levonorgestrel and a skin permeation enhancer in a polyacrylatepressure sensitive adhesive (PSA); (b) the composition comprises atleast one component that contributes to oxidative degradation of thelevonorgestrel, wherein the at least one component is one or more of (i)the polyacrylate PSA, (ii) the skin permeation enhancer wherein theenhancer comprises DMSO, and (iii) polyvinyl pyrrolidone (PVP) or a PVPcopolymer; and (c) (i) the anti-oxidant is not a sulfoxide or a fattyacid; and (iii) the anti-oxidant protects against oxidative degradationof the levonorgestrel by the one or more of the PSA, the DMSO and thePVP or PVP copolymer.
 16. The method of claim 15, comprising adding ananti-oxidant selected from Vitamins A, C, D, and E, carotenoids,flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene(BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallicacid and esters thereof, salicylic acid and esters thereof, sulfites, orany combination thereof.
 17. The method of claim 15, comprising addingan anti-oxidant selected from sodium bisulfite, sodium sulfite,isopropyl gallate, Vitamin C, Vitamin E, BHA, BHT,pentaerythritoltetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate),tris(2,4-di-tert-butylphenyl)phosphite or any combination thereof. 18.The method of claim 15, wherein the composition lacks an estrogen. 19.The method of claim 15, wherein the composition comprises a PVPcopolymer that is PVP/VA.
 20. The method of claim 15, wherein thecomposition further comprises one or more other skin permeationenhancers selected from a fatty (C₈-C₂₀) alcohol ester of a hydroxylacid, a lower (C₁-C₄) alkyl ester of a hydroxyl acid, and a C₆-C₁₈ fattyacid.